2013 Mystery Molecule

December

This giant molecule helps various proteins form their correct structure but its own structure was unknown – until crystallographic data was analyzed using computer modeling recently recognized the Nobel Prize committee. Can you guess what it is?

CCT (chaperonin containing TCP1)

The 2013 Nobel Prize in Chemistry was awarded to Drs. Martin Karplus, Michael Levitt, and Arieh Warshel "for the development of multi-scale models for complex chemical systems." A great example is the recent report by Dr. Levitt and his colleagues describing the use of such modeling to predict the structure of this chaperonin, which consists of two stacked rings of eight subunits each. Contact with certain proteins (such as actin or tubulin) opens a chamber within which the protein is coaxed into folding in a way that will allow it to be functional. The exact structure of the CCT complex itself, however, was not well understood because crystallography could not achieve the necessary resolution. Using computer modeling, the investigators tested the fit of millions of possible side-chains until they found ones that best fit the crystallographic data.

November

This molecule is not the original one used by Ruth Benerito, who died last month, to introduce permanent press to the world, but it is in the same family and has largely replaced her original one as a cellulose cross-linker. Can you guess what it is?

Dimethylol dihydroxy ethylene urea (DMDHEU)

When cloth made of cotton becomes moist, the hydrogen bonds that hold the cellulose polymers in place begin to break and the polymers shift, creating a wrinkle. Ruth Benerito developed a method to keep this from happening using formaldehyde to crosslink the fibers. (Formaldehyde, of course, also "fixes" tissue by crosslinking protein.) Early "permanent press" fabrics had a rough texture and often smelled of formaldehyde. Although a number of improvements have been introduced into the process of treating fabric, a major advance has been the replacement of formaldehyde with DMDHEU, which provides a more "natural" feel (and is less smelly).

October

This molecule, made from an opiate found in cough syrup, has just arrived from Russia – but not "with love". Can you guess what it is?

Desomorphine (Dihydrodesoxymorphine)

This opioid is a derivative of morphine but it can be easily made using codeine, similarly to the way methamphetamine can be easily made from pseudoephedrine. However, Walter White is not the culprit. Drug addicts in Siberia began to manufacture desomorphine because of the scarcity of heroin, and its use is widespread in Russia. The compound has just started to be used by American drug addicts. Its street name is krokodil, because of an unusual side effect that renders the skin scaly like that of the famous reptile. It also leads to severe tissue damage and can result in gangrene.

September

Recent use of thi​s molecule has been almost universally condemned. Can you guess what it is?

Sarin

Sarin is an organophosphate, similar to compounds used in various insecticides, that inhibits acetylcholinesterase, the enzyme that degrades acetylcholine. Exposure causes pathologic muscle contraction which quickly leads to respiratory paralysis and death. It is very volatile and has been classified as a weapon of mass destruction. Its use in Syria in August 2013, reportedly by the Syrian government against civilians in territory held by rebel fighters, created a political crisis which is still not completely resolved.

August

Millions of Americans will be spraying this molecule on their skin this month. Can you guess what it is?

N,N-dimethyl-meta-toluamide (DEET)

DEET is produced by converting meta-toluate (meta-benzoic acid) to the corresponding acyl chloride and allowing it to react with diethylamine. It was developed by the U.S. Army for use as an insect repellent and is now widely used in commercial sprays and lotions, especially those marketed for protection against mosquito bites. Although it was originally thought to hide the odor of human sweat (which is attractive to mosquitoes), recent evidence indicates that it really is a repellent. We hope that your summer was enjoyable and relatively free of insect bites.

July

In the opening plenary of this year's AACC annual meeting, Dr. C. Ronald Kahn from the Joslin Diabetes Center in Boston will be talking a lot about this molecule. Can you guess what it is?

GLUT4 (Glucose Transporter 4)

Dr. Kahn discussed how binding of insulin to the insulin receptor in fat cells initiates a series of alterations in signal transduction proteins allowing this glucose transporter to be expressed on the cell surface. Studies in two strains of mice (one of which are prone to obesity while the other is resistant) have helped to elucidate some of the molecular mechanisms underlying Type 2 diabetes and the metabolic syndrome. A surprise was the finding that the mouse's microbiome influences this process, which was a nice tie-in with the final plenary of the meeting by Dr. Jeffrey Gordon from Washington University. If you attended the annual meeting, we hope that you had a productive one and will look forward to seeing you next year in Chicago.

June

Last month, the Supreme Court ruled unanimously that an Indiana farmer had violated a patent involving this molecule. Can you guess what it is?

Glyphosphate

The addition of phosphonic acid to glycine forms this herbicide marketed as "Roundup" by Monsanto in the 1970s. Although its patent on the herbicide has expired, Monsanto controls the technology used to make transgenic soybeans that are resistant to it. Farmers sign a contract stating that they will not save seeds for replanting, requiring them to buy new seeds from Monsanto each year. The Indiana farmer reused seeds for several years, and his defense was based in part on the fact that he did not do the reproducing; the seeds did. We hope that the weeds in your garden are still sensitive to glyphosphate treatment.

May

Dr. Rita Levi-Montalcini, who died recently at her home in Italy, never married and had no children but she was the "mother" of this incredibly important molecule. Can you guess what it is?

Nerve Growth Factor (NGF)

NGF supports the survival and development of neurons. It is one of a family of such proteins now termed neurotrophins and, of course, the first example of an enormously important type of protein that targets certain cells for tender loving care. Dr. Levi-Montalcini discovered NGF with Dr. Stanley Cohen at Washington University in St. Louis in the early 1950s, and eventually won the Nobel prize for her work. Because of its ability to prevent nerve degeneration, NGF is currently being tested as a potential treatment for a variety of neurodegenerative disorders. Supposedly Dr. Levi-Montalcini dosed herself every day and credited NGF for keeping her mind alert until she died at 103 years of age.

April

Although the news from last month's conference in Atlanta about a baby "cured" of HIV made a big splash, another discovery concerning this molecule is more likely to lead to a real cure. Can you guess what it is?

Mellitin

This short (26 amino acid) peptide is the active ingredient in bee venom. It inhibits membrane ion pumps and leads to cellular disruption, killing cells. Investigators at Washington University in St. Louis recently showed that nanoparticles containing mellitin were able to disrupt the membranes of HIV, preventing infection of T cells. The initial suggested utility of this discovery is the incorporation of these nanoparticles into vaginal gel as they did not appear to affect vaginal wall cell viability.

March

The study of the Mediterranean diet in the New England Journal of Medicine currently making waves used this biomarker to monitor compliance. Can you guess what it is?

Hydroxytyrosol

The study found that the Mediterranean diet reduced cardiovascular risk more significantly than a low-fat diet but it has been criticized for the fact that the control group did not really reduce their fat intake. To monitor compliance with the Mediterranean diet, the investigators tested the urine for hydroxytyrosol, a phenylethanoid found in the olive plant that it a potent anti-oxidant. Hydroxytyrosol esters of elenolic acid are present in olive oil at a very high concentration.

February

A recent decision by a court of appeals for the second circuit involving this molecule may have ramifications for the way in which manufacturers discuss their products with physicians. Can you guess what it is?

Sodium Oxybate (Xyrem ®)

This drug is approved by the FDA for treatment of narcolepsy but may be used for several other "off-label" uses, including insomnia and fibromyalgia. A sales representative was convicted for discussing such indications with a doctor who was a government informant but the recent decision overturned that conviction because it violated the First Amendment right of freedom of speech. Although it is unlikely that IVD manufacturers will suddenly start to talk to laboratorians about similar "off-label" uses of FDA-approved laboratory tests, the FDA will probably not pursue similar convictions as aggressively until this is resolved, possibly by the Supreme Court.

January

The FDA recently approved an oral version of this molecule – a member of a new class of drugs for treatment of rheumatoid arthritis that inhibit a kinase named, as is this month, for a Roman god. Can you guess what it is?

Tofacitinib (Xeljanz ®)

Tofacitinib is an inhibitor of one of the Janus kinase (JAK) enzymes. This family of kinases phosphorylate cell surface receptors and other signaling molecules when the cell surface receptor binds its ligand. The signaling molecules then move to the nucleus to activate the appropriate genes. When the first one was discovered, it was called "just another kinase" but then the name "Janus" kinase was applied because these protein kinases are arranged in pairs on the intracellular portion of the receptors, facing each other. (Janus, for whom January is named, was a two-faced Roman god.) Tofacitinib inihibits signal transduction of a number of receptors involved in activating the immune system (such as IL-2) and has been used to treat autoimmune disorders such as rheumatoid arthritis. The new oral form of the drug will mean it can be used more easily.